The association of long-term outcome and biological sex in patients with acute heart failure from different geographic regions.

AIMS: Recent data from national registries suggest that acute heart failure (AHF) outcomes might vary in men and women, however, it is not known whether this observation is universal. The aim of this study was to evaluate the association of biological sex and 1-year all-cause mortality in patients with AHF in various regions of the world. METHODS AND RESULTS: We analysed several AHF cohorts including GREAT registry (22 523 patients, mostly from Europe and Asia) and OPTIMIZE-HF (26 376 patients from the USA). Clinical characteristics and medication use at discharge were collected. Hazard ratios (HRs) for 1-year mortality according to biological sex were calculated using a Cox proportional hazards regression model with adjustment for baseline characteristics (e.g. age, comorbidities, clinical and laboratory parameters at admission, left ventricular ejection fraction). In the GREAT registry, women had a lower risk of death in the year following AHF [HR 0.86 (0.79-0.94), P < 0.001 after adjustment]. This was mostly driven by northeast Asia [n = 9135, HR 0.76 (0.67-0.87), P < 0.001], while no significant differences were seen in other countries. In the OPTIMIZE-HF registry, women also had a lower risk of 1-year death [HR 0.93 (0.89-0.97), P < 0.001]. In the GREAT registry, women were less often prescribed with a combination of angiotensin-converting enzyme inhibitors and beta-blockers at discharge (50% vs. 57%, P = 0.001). CONCLUSION: Globally women with AHF have a lower 1-year mortality and less evidenced-based treatment than men. Differences among countries need further investigation. Our findings merit consideration when designing future global clinical trials in AHF.

Clinical features and outcome in hospitalized heart failure in Japan (from the ATTEND Registry).

BACKGROUND: Hospitalized heart failure (HHF) is a critical issue in Japan. To improve its management and outcomes, the clinical features, in-hospital management, and outcomes should be analyzed to improve the guidelines for HHF. METHODS AND RESULTS: The acute decompensated heart failure syndromes (ATTEND) registry is the largest study of HHF in Japan. The present report covers the clinical features and in-hospital management of HHF patients. The data from 4,842 enrolled patients have demonstrated that most Japanese HHF patients are elderly, with new onset, and a history of hypertension and orthopnea on admission. During hospitalization, furosemide and carperitide were commonly used and the length of stay was extremely long (mean 30 days), with 6.4% in-hospital mortality. CONCLUSIONS: The findings of the present study suggest the following: (1) the focus for hypertensive elderly and diabetic patients should be on primary prevention of HHF,(2) more intensive management with noninvasive positive pressure ventilation should be performed at the urgent stage, (3) it is necessary to clarify the clinical benefit of carperitide and angiotensin-receptor blockers, because they are commonly used in Japan, and (4) it is necessary to clarify the relationship between in-hospital mortality and length of stay from the viewpoint of both outcome and cost of patient care.

Activation of PKN mediates survival of cardiac myocytes in the heart during ischemia/reperfusion.

RATIONALE: The function of PKN, a stress-activated protein kinase, in the heart is poorly understood. OBJECTIVE: We investigated the functional role of PKN during myocardial ischemia/reperfusion (I/R). METHODS AND RESULTS: PKN is phosphorylated at Thr774 in hearts subjected to ischemia and reperfusion. Myocardial infarction/area at risk (MI/AAR) produced by 45 minutes of ischemia and 24 hours of reperfusion was significantly smaller in transgenic mice with cardiac-specific overexpression of constitutively active (CA) PKN (Tg-CAPKN) than in nontransgenic (NTg) mice (15+/-5 versus 38+/-5%, P<0.01). The number of TUNEL-positive nuclei was significantly lower in Tg-CAPKN (0.3+/-0.2 versus 1.0+/-0.2%, P<0.05). Both MI/AAR (63+/-9 versus 45+/-8%, P<0.05) and the number of TUNEL-positive cells (7.9+/-1.0 versus 1.3+/-0.9%, P<0.05) were greater in transgenic mice with cardiac-specific overexpression of dominant negative PKN (Tg-DNPKN) than in NTg mice. Thr774 phosphorylation of PKN was also observed in response to H(2)O(2) in cultured cardiac myocytes. Stimulation of PKN prevented, whereas inhibition of PKN aggravated, cell death induced by H(2)O(2), suggesting that the cell-protective effect of PKN is cell-autonomous in cardiac myocytes. PKN induced phosphorylation of alpha B crystallin and increased cardiac proteasome activity. The infarct reducing effect in Tg-CAPKN mice was partially inhibited by epoxomicin, a proteasome inhibitor. CONCLUSIONS: PKN is activated by I/R and inhibits apoptosis of cardiac myocytes, thereby protecting the heart from I/R injury. PKN mediates phosphorylation of alpha B crystallin and stimulation of proteasome activity, which, in part, mediates the protective effect of PKN in the heart.

Rapid evaluation by lung-cardiac-inferior vena cava (LCI) integrated ultrasound for differentiating heart failure from pulmonary disease as the cause of acute dyspnea in the emergency setting.

BACKGROUND: Rapid and accurate diagnosis and management can be lifesaving for patients with acute dyspnea. However, making a differential diagnosis and selecting early treatment for patients with acute dyspnea in the emergency setting is a clinical challenge that requires complex decision-making in order to achieve hemodynamic balance, improve functional capacity, and decrease mortality. In the present study, we examined the screening potential of rapid evaluation by lung-cardiac-inferior vena cava (LCI) integrated ultrasound for differentiating acute heart failure syndromes (AHFS) from primary pulmonary disease in patients with acute dyspnea in the emergency setting. METHODS: Between March 2011 and March 2012, 90 consecutive patients (45 women, 78.1 ± 9.9 years) admitted to the emergency room of our hospital for acute dyspnea were enrolled. Within 30 minutes of admission, all patients underwent conventional physical examination, rapid ultrasound (lung-cardiac-inferior vena cava [LCI] integrated ultrasound) examination with a hand-held device, routine laboratory tests, measurement of brain natriuretic peptide, and chest X-ray in the emergency room. RESULTS: The final diagnosis was acute dyspnea due to AHFS in 53 patients, acute dyspnea due to pulmonary disease despite a history of heart failure in 18 patients, and acute dyspnea due to pulmonary disease in 19 patients. Lung ultrasound alone showed a sensitivity, specificity, negative predictive value, and positive predictive value of 96.2, 54.0, 90.9, and 75.0%, respectively, for differentiating AHFS from pulmonary disease. On the other hand, LCI integrated ultrasound had a sensitivity, specificity, negative predictive value, and positive predictive value of 94.3, 91.9, 91.9, and 94.3%, respectively. CONCLUSIONS: Our study demonstrated that rapid evaluation by LCI integrated ultrasound is extremely accurate for differentiating acute dyspnea due to AHFS from that caused by primary pulmonary disease in the emergency setting.

Hypotonic swelling-induced activation of PKN1 mediates cell survival in cardiac myocytes.

Hypotonic cell swelling in the myocardium is induced by pathological conditions, including ischemia-reperfusion, and affects the activities of ion transporters/channels and gene expression. However, the signaling mechanism activated by hypotonic stress (HS) is not fully understood in cardiac myocytes. A specialized protein kinase cascade, consisting of Pkc1 and MAPKs, is activated by HS in yeast. Here, we demonstrate that protein kinase N1 (PKN1), a serine/threonine protein kinase and a homolog of Pkc1, is activated by HS (67% osmolarity) within 5 min and reaches peak activity at 60 min in cardiac myocytes. Activation of PKN1 by HS was accompanied by Thr(774) phosphorylation and concomitant activation of PDK1, a potential upstream regulator of PKN1. HS also activated RhoA, thereby increasing interactions between PKN1 and RhoA. PP1 (10(-5) M), a selective Src family tyrosine kinase inhibitor, significantly suppressed HS-induced activation of RhoA and PKN1. Constitutively active PKN1 significantly increased the transcriptional activity of Elk1-GAL4, an effect that was inhibited by dominant negative MEK. Overexpression of PKN1 significantly increased ERK phosphorylation, whereas downregulation of PKN1 inhibited HS-induced ERK phosphorylation. Downregulation of PKN1 and inhibition of ERK by U-0126 both significantly inhibited the survival of cardiac myocytes in the presence of HS. These results suggest that a signaling cascade, consisting of Src, RhoA, PKN1, and ERK, is activated by HS, thereby promoting cardiac myocyte survival.

Risk of sudden death in end-stage hypertrophic cardiomyopathy.

BACKGROUND: It remains unclear whether end-stage hypertrophic cardiomyopathy (HCM) is associated with as high a rate of sudden death as occurs among HCM patients with preserved left ventricular (LV) systolic function. The purpose of this study was to evaluate the incidence of sudden death among patients with end-stage HCM and to identify high-risk end-stage patients. METHODS AND RESULTS: A total of 490 consecutive patients with HCM, who were diagnosed and followed-up at our hospital, were analyzed retrospectively. End-stage HCM was defined by an LV ejection fraction <50% on echocardiography during follow-up. Among the 490 HCM patients, 43 patients (8.8%) were diagnosed as having end-stage HCM during a mean follow-up period of 12 ± 7 years after the initial diagnosis. During a mean follow-up period of 5 ± 3 years after progression to end-stage HCM, sudden death occurred in 21 of 43 patients (47%). Cox proportional hazards analysis identified syncope as an independent predictor of sudden death (hazard ratio = 6.15; 95% confidence interval, 2.40-15.75; P < .001). CONCLUSIONS: This study demonstrated that patients with end-stage HCM have a high incidence of sudden death. Therefore, it is suggested that an aggressive therapeutic strategy to counter sudden death should be considered for patients with end-stage HCM.

Acute decompensated heart failure syndromes (ATTEND) registry. A prospective observational multicenter cohort study: rationale, design, and preliminary data.

Acute heart failure syndromes (AHFS) are likely to increase in the future, and the high readmission rate of patients with AHFS is an important issue in Western countries. However, there are very few published epidemiological studies on AHFS in the Asia Pacific region. Because AHFS are heterogeneous, the characteristics, clinical profile, and management of AHFS should be clarified in an epidemiological study. The acute decompensated heart failure syndromes (ATTEND) registry is a prospective, observational, multicenter cohort study being performed in Japan and is the first epidemiological study of AHFS in the Asia Pacific region. This study is designed to investigate several aspects of AHFS as follows: (1) the registry allows patient-based data collection for precise evaluation of patient characteristics and short-term outcomes, including the readmission rate; (2) confirmation of clinical assessments can be performed, and new clinical assessments can be created; and (3) feedback allows the modification of guidelines for clinical management. The present report describes the clinical characteristics of patients with AHFS in Japan based on the preliminary data collected in this study, and the similarities and differences in characteristics of these patients compared with those in Western countries. Although most of the patient characteristics did not differ from those reported in Western studies, there are some unique findings in this study, including a high rate of treatment with carperitide (69.4%) and angiotensin II receptor blockers (53.9%) at discharge and a longer hospital stay (median 21 days). The ATTEND registry is designed to provide valuable information to clarify the characteristics of patients with AHFS to improve their management.

Sex Differences in New York Heart Association Functional Classification and Survival in Acute Heart Failure Patients With Preserved or Reduced Ejection Fraction.

BACKGROUND: The aim of this study was to evaluate the influence of sex on the relationship between the New York Heart Association (NYHA) functional classification and survival in acute decompensated heart failure (HF) patients with preserved or reduced ejection fraction (EF). METHODS: Of 4842 patients enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, 4717 (2730 men and 1987 women) were investigated to assess the association of sex, NYHA functional class, and preserved or reduced EF with all-cause death. Men and women were divided into 6 groups based on left ventricular EF (preserved or reduced) and NYHA functional class (II, III, or IV) at admission. RESULTS: Among both sexes with preserved EF, multivariable analysis confirmed that NYHA functional class IV was associated with a significantly higher risk of all-cause death than NYHA functional class II. Similarly, in women with reduced EF, NYHA functional class IV was a significant predictor of all-cause death compared with class II. However, in men with reduced EF, the adjusted risk of all-cause death was similar for those in NYHA functional classes II, III, and IV. Furthermore, the interaction between sex and NYHA functional classes II to IV was statistically significant for all-cause death in reduced EF patients (P for interaction = 0.037), but not in preserved EF patients (P for interaction = 0.711). CONCLUSIONS: NYHA functional class IV was a significant predictor of all-cause death in both sexes with preserved EF, whereas NYHA functional class IV was a significant predictor of all-cause death in women, but not in men, with reduced EF.

Acute efficacy and safety of intravenous administration of nicorandil in patients with acute heart failure syndromes: usefulness of noninvasive echocardiographic hemodynamic evaluation.

This study was conducted to evaluate the acute efficacy and safety of intravenous administration of nicorandil in patients with acute heart failure syndromes (AHFS), under noninvasive hemodynamic assessment with transthoracic Doppler echocardiography. After baseline hemodynamic measurements, initial bolus and 48-hour continuous intravenous nicorandil infusion were begun in 14 hospitalized patients with AHFS. After 2-hour infusion, estimated pulmonary capillary wedge pressure was reduced from 21.4 +/- 6.4 to 17.5 +/- 5.2 mm Hg (P < 0.05) and was sustained for 48 hours to 16.2 +/- 5.5 mm Hg (P < 0.05). A significant increase in estimated cardiac output was observed at 2 hours, from 4.0 +/- 1.0 to 4.8 +/- 1.3 L/min (P < 0.05). This increase was sustained for 48 hours to 5.8 +/- 1.8 L/min (P < 0.05). The high blood pressure (BP) group (baseline systolic BP > or = 140 mm Hg, n = 7) exhibited significant decrease in systolic BP (from 156.7 +/- 14.2 to 135.4 +/- 13.3 mm Hg, P < 0.05). In contrast, there was no change in systolic BP in the low BP group (baseline systolic BP < 140 mm Hg, n = 7) over 48 hours (from 107.6 +/- 20.4 to 107.7 +/- 17.4 mm Hg, P = not significant). The results of this study demonstrate the acute hemodynamic efficacy and safety of intravenous administration of nicorandil and also suggest the usefulness of noninvasive echocardiographic hemodynamic evaluation in the urgent phase of AHFS.

Systolic blood pressure at admission as a predictor of the response to initial carperitide therapy in patients hospitalized for acute decompensated heart failure with left ventricular systolic dysfunction.

PURPOSE: In patients with acute decompensated heart failure (ADHF) and left ventricular systolic dysfunction (LVSD), the role of initial vasodilator therapy remains uncertain. The present study aimed to evaluate the acute efficacy of initial carperitide therapy and to predict its response in ADHF patients with LVSD. METHODS: Twenty-four consecutive patients with ADHF and LVSD were enrolled. Inclusion criteria were a left ventricular ejection fraction < 40%, systolic blood pressure (BP) > 90 mm Hg, and pulmonary capillary wedge pressure >or=18 mm Hg at baseline. Hemodynamic parameters were evaluated by right heart catheterization before and after carperitide infusion. Responders were defined as a >or=30% reduction of pulmonary capillary wedge pressure (PCWP) or a decrease to < 16 mm Hg within 6 h after carperitide infusion. RESULTS: Seventeen (71%) of the 24 patients were responders for initial carperitide therapy. The responders had significantly higher systolic BP and cardiac index at baseline compared with nonresponders. The area under the curve (AUC) for systolic BP was 0.93 and a cut-off value of 120 mm Hg had a sensitivity of 94% and specificity of 86% for predicting the efficacy of carperitide. The AUC for the cardiac index was 0.88 and a cut-off value of 2.30 L/min/m(2) had a sensitivity of 65% and a specificity of 100% for predicting the response to carperitide. CONCLUSIONS: The initial use of carperitide therapy safely reduces PCWP in ADHF patients with LVSD and baseline systolic BP may be useful for predicting the response to initial carperitide therapy for ADHF with LVSD.

Adding High-Dose Spironolactone to Tolvaptan Improves Acute Decompensated Heart Failure Due to Obstructive Hypertrophic Cardiomyopathy and Aortic Stenosis: A Case Report.

BACKGROUND In the setting of acute decompensated heart failure (ADHF), tolvaptan, a selective V2 receptor antagonist, did not alter plasma renin activity or angiotensin II level, but significantly increased plasma aldosterone by the activation of V1ₐ receptor, suggesting that a high-dose mineralocorticoid receptor antagonist (MRA) combined with a V2 receptor antagonist might be of interest, especially in ADHF patients. However, in the setting of ADHF, the short-term and long-term efficacy of a high-dose MRA combined with tolvaptan remains unclear. CASE REPORT An 86-year-old woman with a history of chronic HF with a preserved ejection fraction due to obstructive hypertrophic cardiomyopathy and severe aortic stenosis was transferred to our hospital complaining of persistent dyspnea (New York Heart Association class IV). She did not respond to standard therapy with tolvaptan (15.0 mg/day). However, the present case demonstrated that adding high-dose spironolactone (100 mg/day) to low-dose tolvaptan (15.0 mg/day) is safe and well tolerated, resulting in an increase in urine output and improvement of the symptoms or signs of ADHF in a patient who was refractory to loop diuretics and tolvaptan. CONCLUSIONS The short- and long-term efficacy of high-dose spironolactone combined with low-dose tolvaptan may be associated with an attenuation of the aldosterone level, which is increased through V1ₐ activation by vasopressin during tolvaptan administration.

Association of admission and discharge anemia status with outcomes in patients hospitalized for acute decompensated heart failure: Differences between patients with preserved and reduced ejection fraction.

BACKGROUND: In acute decompensated heart failure patients with a preserved or reduced ejection fraction, the association of admission and discharge anemia status with outcomes remains unclear. METHODS AND RESULTS: Of the 4842 patients enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, 4433 patients (2017 with a preserved and 2416 with a reduced ejection fraction) were examined to investigate associations among the anemia status at admission and discharge (no anemia, developed anemia, resolved anemia, or persistent anemia), a preserved or reduced ejection fraction and the primary endpoint (all-cause death and readmission for heart failure). In the preserved ejection fraction group, adjusted analysis showed that either developed or persistent anemia was associated with a significantly higher risk of the primary endpoint relative to no anemia (hazard ratio: 1.53; 95% confidence interval (CI): 1.11-2.11; p=0.009 and hazard ratio: 1.60; 95% CI: 1.26-2.04; p<0.001, respectively), but there was no association between resolved anemia and the primary endpoint (hazard ratio: 0.98; 95% CI: 0.67-1.45; p=0.937). In the reduced ejection fraction group, either developed or resolved anemia was associated with a tendency toward higher risk of the primary endpoint relative to no anemia (hazard ratio: 1.29; 95% CI: 0.95-1.62; p=0.089, and hazard ratio: 1.31; 95% CI: 0.96-1.77; p=0.085, respectively), while persistent anemia was associated with a significantly higher risk of the primary endpoint relative to no anemia (hazard ratio: 1.36; 95% CI: 1.12-1.65; p=0.002). CONCLUSIONS: In acute decompensated heart failure patients, the association of admission and discharge anemia status with outcomes differs markedly between patients with a preserved or reduced ejection fraction.

Heterogeneous impact of body mass index on in-hospital mortality in acute heart failure syndromes: An analysis from the ATTEND Registry.

BACKGROUND: Although the obesity paradox may vary depending upon clinical background factors such as age, gender, aetiology of heart failure and comorbidities, the reasons underlying the heterogeneous impact of body mass index (BMI) on in-hospital cardiac mortality under various conditions in patients with acute heart failure syndromes (AHFSs) remain unclear. METHODS: Among 4617 hospitalised patients with AHFSs enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, the patient characteristics and in-hospital cardiac mortality rates in those with low BMI (BMI <25 kg/m2, n = 3263) were compared to those with high BMI (BMI ⩾25 kg/m2, n = 1354). RESULTS: Compared to the high-BMI group, the low-BMI group was significantly older, less likely to be male and to have hypertensive or idiopathic dilated aetiologies and more likely to have valvular aetiologies and a history of prior hospitalisation for AHFS. The low-BMI group also had lower prevalence rates of diabetes, dyslipidaemia, hypertension and atrial fibrillation and higher prevalence rates of anaemia and chronic obstructive pulmonary disease. In addition, cardiac mortality was significantly higher in the low-BMI group than in the high-BMI group (5.5 vs. 1.5%, p < 0.001). Logistic regression analysis demonstrated that low BMI was a predictor of cardiac mortality (odds ratio: 3.89, 95% confidence interval: 2.44-6.21). In subgroup analyses, the impact of BMI on cardiac mortality differed depending on the presence of hypertensive aetiology, hypertension, chronic obstructive pulmonary disease and hyponatremia (all p < 0.05), although there were no interactions between the impacts of BMI and age, gender, other aetiologies, prior hospitalisation, diabetes, anaemia, cardio-renal function and in-hospital management. CONCLUSION: It is necessary to appreciate the obesity paradox in AHFS patients, and a patient's heterogeneous background should also be considered.

Effect of Elevated C-Reactive Protein Level at Discharge on Long-Term Outcome in Patients Hospitalized for Acute Heart Failure.

In the acute heart failure (AHF) setting, the usefulness of C-reactive protein (CRP) at admission as a risk marker is challenged by the possible confounding effect of an acute-phase response. We thus evaluated the relation of CRP level at discharge (i.e., after stabilization of AHF) with subsequent postdischarge outcome in patients hospitalized for AHF. The acute decompensated heart failure syndromes study prospectively registered 4,269 hospitalized AHF patients with data on CRP levels at discharge. The median CRP level was 3.1 mg/L (interquartile range 1.1 to 9.5 mg/L). Within 120 days after discharge, only CRP levels in the fourth quartile (≥9.6 mg/L) were independently associated with higher all-cause mortality (adjusted hazard ratio [HR], 1.68) according to multivariable models with first-quartile (≤1.1 mg/L) as the reference. However, the HR for CRP levels in the fourth quartile decreased markedly with time, and CRP levels in the second (1.2 to 3.1 mg/L) and third (3.2 to 9.5 mg/L) quartiles were independently associated with poorer survival after the 120-day follow-up period (adjusted HR, 1.41 and 1.63, respectively). In addition, only CRP levels in the third quartile were independently associated with the composite end point of all-cause death and readmission for AHF after the 120 days of long-term follow-up (adjusted HR, 1.31). In conclusion, our results suggest that a modestly elevated CRP level (approximately 3 to 10 mg/L) at discharge had unique long-term prognostic implications in hospitalized patients with AHF.

Sex Differences in Left Ventricular Cavity Dilation and Outcomes in Acute Heart Failure Patients With Left Ventricular Systolic Dysfunction.

BACKGROUND: In this study we evaluated the influence of sex on the left ventricular end-diastolic dimension (LVEDD) and adverse outcomes in patients hospitalized for acute decompensated heart failure (HF) with a reduced ejection fraction (EF). METHODS: Among the 4842 patients enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, 2367 patients (1607 men and 760 women) discharged alive after hospitalization for acute decompensated HF with a reduced EF (defined as a left ventricular EF < 50%) were investigated to assess the association of sex and LVEDD with the primary end point (all-cause death and readmission for HF after discharge). Men and women were separately divided into LVEDD quartiles at discharge (men: LVEDD ≤ 54, 55-60, 61-65, and ≥ 66 mm; women: LVEDD ≤ 48, 49-54, 55-60, and ≥ 61 mm). The median follow-up period after discharge was 524 (range, 385-785) days. RESULTS: Occurrence of the primary end point did not differ between men and women (37.0% vs 37.2%; P = 0.921). After adjustment for multiple comorbidities including left ventricular EF, men with an LVEDD of 61-65 and ≥ 66 mm had a significantly higher risk of the primary end point than men with an LVEDD ≤ 54 mm, indicating a positive association between a larger LVEDD and adverse outcomes. In contrast, in women, the adjusted risk of the primary end point was comparable among the LVEDD quartiles. CONCLUSIONS: Men and women with acute decompensated HF and a reduced EF might show important differences in relation to the association between left ventricular cavity dilation and outcomes.

Trends and predictors of non-cardiovascular death in patients hospitalized for acute heart failure.

BACKGROUND: Little information is available on non-cardiovascular (CV) death in acute heart failure (AHF) patients. The present study determined the incidence, time course, and factors associated with long-term non-CV death in AHF patients in a real-world setting. METHODS: The ATTEND registry, a nationwide, prospective observational multicenter cohort study, included 4842 consecutive patients hospitalized for AHF. The primary endpoint of the present study was non-CV death. RESULTS: Median follow-up duration from admission was 513 (range, 385-778) days. Over the study period, 1183 patients died; 356 deaths (30.1%) were non-CV related. The proportion of non-CV deaths increased in the later follow-up phase (0-180days, 26.7%; 181-360days, 38.4%; >360days, 36.6%, p<0.001). After adjustment for all variables at baseline, age (hazard ratio [HR] 1.6 per decade, p<0.001) and non-cardiac comorbidities including chronic obstructive pulmonary disease (HR 1.58, p=0.003), history of stroke (HR 1.44, p=0.011), renal insufficiency (HR 1.07, per 10ml/min/1.73m2 decrease in estimated glomerular filtration, p=0.015), and hemoglobin (HR 1.15 per 1.0g/dl decrease, p<0.001) were strongly associated with non-CV death. Other predictors included ischemic etiology (HR 1.33, p=0.023), prior hospitalization for heart failure (HR 1.34, p=0.017), C-reactive protein (HR 1.04, p<0.001), and statin use (HR 0.70, p=0.016). CONCLUSIONS: The incidence of non-CV death was high in patients with AHF, accounting for 30% of long-term mortality. Furthermore, the proportion of non-CV death increased in the later follow-up phase. Better understanding of non-CV death and more comprehensive treatment of non-CV comorbidities are vital to further improving prognosis in AHF patients.

Heart failure oral therapies at discharge are associated with better outcome in acute heart failure: a propensity-score matched study.

AIMS: Heart failure oral therapies (HFOTs), including beta-blockers (BB), renin-angiotensin system inhibitors (RASi) and mineralocorticoid receptor antagonists, administered before hospital discharge after acute heart failure (AHF) might improve outcome. However, concerns have been raised because early administration of HFOTs may worsen patient's condition. We hypothesized that HFOTs at hospital discharge might be associated with better post-discharge survival. METHODS AND RESULTS: The study population was composed of 19 980 AHF patients from the GREAT registry. The primary and secondary outcomes were 90-day and 1-year all-cause mortality, respectively. Survival was estimated with univariate and covariate-adjusted Cox proportional hazards regression models for the whole population and after propensity-score matching. HFOTs at discharge were consistently associated with no excess mortality in the unadjusted and adjusted analyses of the whole and matched cohorts. In the matched cohort, BB and RASi at discharge were associated with lower 90-day mortality risks compared to the respective untreated groups [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.46-0.69; and HR 0.53, 95% CI 0.42-0.66, respectively]. The favourable associations of BB and RASi at discharge with 90-day mortality were present in many subgroups including patients with reduced or preserved left ventricular ejection fraction and persisted up to 1 year after discharge. The combination of RASi and BB was associated with an even lower risk of death than RASi or BB alone. CONCLUSIONS: Administration of HFOTs at hospital discharge is associated with better survival of AHF patients.

Relationship of renal insufficiency and clinical features or comorbidities with clinical outcome in patients hospitalised for acute heart failure syndromes.

BACKGROUND: Renal insufficiency is a well-known predictor of adverse events in patients with acute heart failure syndromes (AHFS). However, it remains unclear whether there are subgroups of AHFS patients in whom renal insufficiency is related to a higher risk of adverse events because of the heterogeneity of this patient population. Therefore, we investigated the relationship between renal insufficiency, clinical features or comorbidities, and the risk of adverse events in patients with AHFS. METHODS AND RESULTS: Of 4842 patients enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, 4628 patients (95.6%) were evaluated in the present study in order to assess the relationship of renal insufficiency and clinical features or comorbidities with all-cause mortality after admission. Renal insufficiency was defined as an estimated creatinine clearance of ⩽40 mL/min (calculated by the Cockcroft-Gault formula) at admission. The median follow-up period after admission was 524 (391-789) days. The all-cause mortality rate after admission was significantly higher in patients with renal insufficiency (36.7%) than in patients without renal insufficiency (14.4%). Stratified analysis was performed in order to explore the heterogeneity of the influence of renal insufficiency on all-cause mortality. This analysis revealed that an ischaemic aetiology and a history of diabetes, atrial fibrillation, serum sodium, and anaemia at admission had significant influences on the relationship between renal insufficiency and all-cause mortality. CONCLUSIONS: The present study demonstrated that the relationship between renal insufficiency and all-cause mortality of AHFS patients varies markedly with clinical features or comorbidities and the mode of presentation due to the heterogeneity of this patient population.

Ischemic or Nonischemic Functional Mitral Regurgitation and Outcomes in Patients With Acute Decompensated Heart Failure With Preserved or Reduced Ejection Fraction.

The aim of this study was to evaluate the association of functional mitral regurgitation (FMR), preserved or reduced ejection fraction (EF), and ischemic or nonischemic origin with outcomes in patients discharged alive after hospitalization for acute decompensated heart failure (HF). Of the 4,842 patients enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, 3,357 patients were evaluated to assess the association of FMR, preserved or reduced EF, and ischemic or nonischemic origin with the primary end point (all-cause death and readmission for HF after discharge). At the time of discharge, FMR was assessed semiquantitatively (classified as none, mild, or moderate to severe) by color Doppler analysis of the regurgitant jet area. According to multivariable analysis, in the ischemic group, either mild or moderate to severe FMR in patients with a preserved EF had a significantly higher risk of the primary end point than patients without FMR (hazard ratio [HR] 1.60; 95% confidence interval [CI] 1.12 to 2.29; p = 0.010 and HR 1.98; 95% CI 1.30 to 3.01; p = 0.001, respectively). In patients with reduced EF with an ischemic origin, only moderate to severe FMR was associated with a significantly higher risk of the primary end point (HR 1.67; 95% CI 1.11 to 2.50; p = 0.014). In the nonischemic group, there was no significant association between FMR and the primary end point in patients with either a preserved or reduced EF. In conclusion, among patients with acute decompensated HF with a preserved or reduced EF, the association of FMR with adverse outcomes may differ between patients who had an ischemic or nonischemic origin of HF.

C-reactive protein level on admission and time to and cause of death in patients hospitalized for acute heart failure.

Aims: We analysed the association between C-reactive protein (CRP) levels measured on admission and timing and cause of death among patients hospitalized for acute heart failure (AHF). Methods and Results: The ATTEND study prospectively registered 4777 hospitalized AHF patients with data on CRP levels on admission. Mortality risks were assessed by univariable and multivariable Cox proportional and non-proportional hazards models. The overall median CRP level was 5.8 mg/L (intertertile range: 2.9-11.8 mg/L). There were significant increases in all-cause, cardiac, and non-cardiac mortalities from the lowest to highest CRP tertiles throughout the follow-up periods. Within 120 days after admission, CRP levels in the highest tertile (>11.8 mg/L) were independently associated with higher all-cause (hazard ratio [HR], 2.21; 95% confidence interval [CI], 1.69-2.88; P < 0.001), cardiac (HR, 1.88; 95% CI, 1.37-2.58; P < 0.001), and non-cardiac (HR, 3.21; 95% CI, 1.94-5.32; P < 0.001) deaths, while levels in the second tertile (2.9-11.8 mg/L) were not associated with poorer survival, compared with levels in the first tertile (<2.9 mg/L). However, in terms of cardiac death, the hazard ratios for patients in the third tertile decreased markedly with time and only CRP levels in second tertile were independently associated with poorer cardiac survival after the follow-up period of 120 days (HR, 1.44; 95% CI, 1.09-1.89; P = 0.011). Conclusions: Markedly elevated CRP levels at admission in patients with AHF may be associated with higher short-term cardiac and non-cardiac mortalities. In addition, modestly elevated CRP levels may be associated with higher mortality, especially cardiac mortality, after 120 days of long-term follow-up.